1. Field of Inventive Subject Matter
The inventive subject matter relates to novel processes for making an epoxy alcohol from an aldehyde, comprising the steps of: (a) adding (i) an organozinc compound or (ii) a divinylzinc compound and an diorganozinc compound to said aldehyde in the presence of a first catalyst to form an allylic alkoxide compound; and (b) epoxidizing said allylic alkoxide compound in the presence of an oxidant and a second catalyst.
2. Background
Epoxides are important intermediates in organic synthesis, as their reactive nature facilitates transformation into many classes of compounds under mild conditions. Epoxy alcohols contain three reactive sites for further elaboration: the carbon bearing the hydroxyl and the two carbons of the oxirane ring. From a synthetic point of view, the large range of possibilities for the three active sites of an epoxy alcohol, which could eventually lead to three consecutive stereogenic centers, makes the epoxy alcohols the most versatile compounds obtained by oxidative olefin methodology. The ability to functionalize epoxy alcohols with excellent control over regiochemistry is what makes these intermediates so valuable. Applicants have developed new methods to prepare epoxy alcohols, most of which are not easily accessible using known methods.
Medications sold as single enantiomers comprise 50 of the 100 top selling drugs, and represent an industry of well over 100 billion dollars per year. The precursors of these medications are chiral substances of high optical purity, which constitute an important class of starting materials for organic and medicinal chemists. Using the stereochemistry of these materials to control generation of subsequent stereogenic centers allows the preparation of biologically and medicinally important target molecules as single enantiomers. Organic compounds of very high optical purity are essential for testing and evaluation of biological activity, because each enantiomer can interact with a distinct site in an organism and elicit very different responses.
Chemical and medical scientists have understood the significance of producing drugs as single enantiomers for many years. As chemists have honed their ability to generate chiral molecules and efficiently analyze their enantiopurity, the FDA has encouraged the pharmaceutical industry to introduce medications as single enantiomers. As a result of the FDA's actions, medications are increasingly being synthesized, tested, and sold as single enantiomers.
The production of medications as single enantiomers has been accomplished primarily by four different techniques: 1) use of natural sources as starting materials, 2) resolution of racemates, 3) chiral auxiliary chemistry, and 4) asymmetric catalysis. Increasingly, the use of chiral catalysts is displacing the application of chiral reagents and chiral auxiliaries in the asymmetric synthesis of natural and unnatural products. An active asymmetric catalyst enables the chemist to prepare large quantities of material with high enantiopurity from small amounts of enantiopure material, without the need to cleave and recover the chiral auxiliary. Despite the recent advances in asymmetric synthesis, many formidable challenges remain. Predominant among these is the development of methods that enable rapid increases in molecular complexity with minimal isolation and purification. Such multicomponent tandem reactions are in high demand, because they enhance synthetic efficiency and facilitate diversity oriented synthesis. The development of experimentally simple, efficient, and highly enantio- and diastereoselective catalysts for the generation of C—C and C—O bonds in chiral epoxy alcohols is a principal result of the inventive subject matter.
Enantioenriched epoxy alcohols are among the most versatile and utile intermediates in asymmetric organic synthesis. These substrates readily undergo regio- and stereoselective ring-opening reactions with a wide array of nucleophiles. As a result, they have been employed frequently in the synthesis of natural and non-natural products. Much interest has been shown, therefore, in developing regio- and stereoselective synthetic methods for this class of compounds. In the prior art, chiral epoxy alcohols have typically been synthesized by selective epoxidation of the corresponding allylic alcohols, a process which can take place under reagent control, in the case of achiral allylic alcohols, or under substrate control, in the case of chiral allylic alcohols.
The Sharpless-Katsuki epoxidation. The history of the Sharpless-Katsuki epoxidation and its impact on synthetic organic chemistry and asymmetric catalysis is well known. The titanium catalyzed asymmetric epoxidation of allylic alcohols has remained virtually unchanged and unchallenged since its discovery in 1980. As shown in Scheme P-1, the Sharpless-Katsuki epoxidation involves a combination of substoichiometric titanium tetraisopropoxide, tert-butyl hydroperoxide (TBHP), a dialkyl tartrate ligand, and an achiral allylic alcohol. The reaction gives excellent enantioselectives for a variety of allylic alcohols (usually >90%), as demonstrated by hundreds of reported applications of this reaction in the last twenty years. Either enantiomer of the epoxy alcohol can be easily prepared, because both enantiomers of the ligands are commercially available.

As the Sharpless-Katsuki epoxidation became widely employed, the chemistry of 2,3-epoxy alcohols was greatly expanded.
Particularly relevant to the inventive subject matter is the use of a Sharpless-Katsuki epoxidation catalyst with allylic alcohols containing a preexisting stereocenter at the carbanol carbon, as shown in Scheme P-2. In the kinetic resolution (“KR”) of racemic allylic alcohols, one enantiomer of the substrate is epoxidized much faster than the other, with kfast/kslow (defined as krel) often over 50. Although it is usually the resolved allylic alcohol that is desired, the epoxy alcohol can be obtained with good enantio- and diastereoselectivity in most cases. The erythro diastereomer is formed when the substrate and catalyst are matched, whereas the mismatched combination usually gives either the threo or erythro diastereomer with low diastereoselectivity. The major drawbacks to the Sharpless-Katsuki method are 1) the racemic allylic alcohol must be synthesized, isolated, and purified beforehand, 2) the maximum yield in any kinetic resolution is 50%, and 3) the epoxy alcohol product can be difficult to separated from the unreacted allylic alcohol. Related epoxy alcohols have also been prepared by oxidation of 2,3-epoxy alcohols to the aldehyde, followed by addition of an organometallic reagent. Mixtures of diastereomers are observed in most of these reactions. The inventive subject matter addresses these disadvantages directly, and is complementary to the Sharpless-Katsuki KR in that the threo diastereomer is formed, in contrast to the erythro diastereomer under Sharpless conditions.

Currently, the asymmetric epoxidation introduced by Sharpless and Katsuki, is the foremost method for synthesizing epoxy alcohols from prochiral allylic alcohols. The Sharpless-Katsuki asymmetric epoxidation employs catalytic titanium tetraisopropoxide, tartrate ester ligands, 4 Å molecular sieves, and tert-butyl hydroperoxide (TBHP) in the construction of enantioenriched epoxy alcohols. The ability to efficiently synthesize these useful chiral building blocks led to new synthetic disconnections and, thereby, transformed the approaches taken to synthesize natural products, making it one of the most useful reactions in organic synthesis.
In contrast to the synthesis of epoxy alcohols from prochiral allylic alcohols, the synthesis of epoxy alcohols containing a stereogenic center at the carbinol carbon from achiral materials requires that three contiguous stereocenters be generated diastereo- and enantioselectively. This transformation is currently performed in a two-step process involving synthesis, isolation, and purification of the enantioenriched allylic alcohol, followed by a directed epoxidation.
Further, the Sharpless-Katsuki KR has significant limitations. As with all kinetic resolutions, the isolated yield of the epoxy alcohol product can be no greater than 50%, and in most cases, it is significantly less. This transformation is performed on a racemic allylic alcohol, and the resulting enantioenriched starting material and the epoxy alcohol product must be separated by column chromatography. In order to obtain the epoxy alcohol with high enantiomeric excess (“ee”), the reaction must be quenched at low conversion, because the ee of the epoxy alcohol decreases over the course of the KR. The epoxy alcohol is therefore not usually obtained directly from the Sharpless KR; rather the enantioenriched allylic alcohol is first isolated. After purification, the allylic alcohol is subjected to a directed epoxidation to yield the desired epoxy alcohol. The lack of efficient methods for the synthesis of this class of epoxy alcohols has prevented their widespread implementation as key intermediates in organic synthesis. An alternate approach to the Sharpless-Katsuki KR is therefore required.
Epoxidation of the isolated enantioenriched secondary allylic alcohols is generally performed using an organic peracid, such as meta-chloroperbenzoic acid (mCPBA), or with a transition-metal catalyst in combination with a stoichiometric oxidant. Good to excellent diastereoselectivities have been achieved with cyclic allylic alcohols using a wide range of oxidizing agents. Acyclic allylic alcohols have proven to be a more synthetically challenging class of chiral building blocks, because the increased conformational freedom permits directed epoxidation to occur at both diastereotopic faces of the olefin.
In the prior art, cyclic allylic alcohols and acyclic allylic alcohols having substitution on the olefin such that significant A1,3 or A1,2 strain exists in one of the diastereomeric transition states have been produced with good to excellent diastereoselectivities. Thus, A1,3 strain encountered in the transition state leading to the minor diastereomer can result in high diastereoselectivity for allylic alcohols that are Z-substituted with respect to the carbanol moiety. Likewise, substrates with substitution geminal to the carbanol group can exhibit A1,2 strain in one of the diastereomeric transition states and be epoxidized with high diastereoselectivity. In the prior art, allylic alcohols containing disubstituted (E)-olefins were among the most difficult substrates for directed epoxidation. In the absence of significant A1,3 and/or A1,2 strain in the diastereomeric transition states, diastereoselectivities for these substrates were typically less than 2:1 with both peracid- and transition-metal catalyzed epoxidation reactions.
As shown in Scheme P-3, we expected that the peracid associates with the allylic alcohol via hydrogen bonding with a dihedral angle of approximately 120°, while in the case of vanadium- and titanium-based peroxide catalysts, the binding of the allylic alkoxide to the metal is expected to favor a dihedral angle of 40-50° and 70-90°, respectively. This dihedral angle determines the spatial relationships between the substituents on the olefin (R2, R3, and R4) and the substituent at the stereogenic center (R1) in the transition state. Therefore, the preferred diastereomer of the product epoxy alcohol and the extent to which it dominates may differ for a given allylic alcohol substrate, depending upon the epoxidizing agent used. For any given epoxidizing agent, the favored diastereomer is dictated by the substitution pattern of the allylic alcohol, which determines whether A1,2 or A1,3 strain is the dominant steric interaction in the transition state.

In the inventive subject matter, titanium catalysts are preferentially employed. When R=alkyl and R1═R2═H, there is no A1,2 or A1,3 strain in either transition state.
Thus, substitution on the olefin, such that significant A1,2 or A1,3 strain exists in one of the diastereomeric transition states, can lead to strong preference for formation of one diastereomer over the other; however, the degree of selectivity is dictated by the type of oxidant used (Table P-1). In the case where A1,3 strain exists in one of the diastereomeric transition states, the threo diastereomer predominates (Table P-1, entries 1 and 2). On the other hand, the major diastereomer is the erythro in the case where A1,2 strain is present in one of the diastereomeric transition states (Table P-1, compound 3). With trans-disubstituted olefins, there is no significant source of allylic strain in either diastereomeric transition state. This leads to low diastereoselectivities, with neither the erythro nor the threo diastereomer consistently predominating (Table P-1, compound 4).
TABLE P-1Diastereomeric ratios for the directed epoxidation of chiralsecondary allylic alcohols with various oxidizing agents.Diastereomeric Ratios (erthyro:threo)Ti(OiPr)4VO(acac)2EntrySubstratet-BuOOHt-BuOOHmCPBA1  1:10  1:2.4  1:19 2  1:19  1:6.1  1:19 33.5:1 19:11.2:1   4  1:1.92.4:1   1:1.8
Differences in diastereoselectivity for a given allylic alcohol or allylic alkoxide substrate with different epoxidation methods can be explained by examination of the degree of allylic strain in the diastereomeric epoxidation transition states. The dihedral angle, C═C—C—O, of the substrate determines the spatial relationships between the substituents on the olefin (R2, R3 and R4) and the substituent at the stereogenic center (R1) in the transition states (Scheme P-4). The two diastereomeric transition states for epoxidation with Ti(OiPr)4/TBHP are shown in Scheme P-4. For that system, the titanium peroxide catalyst binds to the allylic alkoxide and delivers the oxidant with a dihedral angle of 70°-90°. This leads to Ti(OiPr)4/TBHP being more diastereoselective in the case of A1,3 strain (Table P-1, entries 1, 2) than in the case of A1,2 strain (compound 3).

Sharpless has previously demonstrated the application of the KR to a bis(allylic alcohol) for the synthesis of an allylic epoxy alcohol (Scheme P-5). In that case, the starting material, a racemic bis(allylic alcohol), has eight different olefinic faces at which epoxidation can occur. The relative rate of epoxidation of a disubstituted versus a monosubstituted allylic olefin with the Sharpless catalyst is sufficiently large in this example such that high selectivity is observed for the more electron rich, disubstituted double bond. Although this reaction displays the power of the Sharpless catalyst, the yield and synthetic efficiency remain low.

Epoxy alcohols bearing additional functionality, such as allylic epoxy alcohols, are of interest for their increased synthetic potential in the construction of natural products. These compounds contain three different functional groups: an olefin, a carbinol, and the epoxide. This increased functionality makes them especially useful intermediates, but it also makes their synthesis more difficult. As in the case of the epoxy alcohol substrates discussed previously, the issues of enantio- and diastereoselectivity for the generation of three contiguous stereocenters must be addressed. In addition, there are chemoselectivity issues involving differentiation of the two allylic double bonds in the synthesis of allylic epoxy alcohols.
Jacobsen-Katsuki epoxidation. Ten years after the seminal work of Sharpless and Katsuki, Jacobsen and Katsuki introduced catalysts for the epoxidation of isolated olefins based on (salen)Mn complexes, as shown in Scheme P-6. A variety of oxidants can be employed in the epoxidation reaction, with NaOCl and iodosylbenzene being most common. Additives such as N-oxides prolong catalyst lifetimes and increase enantioselectivities. The best substrates are conjugated (Z)-disubstituted olefins, while (E)-isomers give lower enantioselectivities. Terminal olefins remain a challenging class of substrates for these catalysts. It has been found that the (salen) Cr-based catalysts exhibit higher levels of enantioselectivity with (E)-disubstituted olefins, while a (salen)Ru(NO) system introduced by Katsuki exhibited high enantioselectivities with (E)- and (Z)-conjugated olefins.

An excellent catalyst has been introduced by Jacobsen and coworkers for the kinetic resolution of terminal epoxides. These catalysts, based on (salen)Co(OAc), exhibit very large relative rates of reaction with enantiomeric epoxides.
Chiral dioxirane epoxidation catalysts. A drawback of the (salen)Mn-based catalysts of Jacobsen and Katsuki is the low levels of enantioselectivity with (E)-disubstituted olefins. It was found, however, that (E)-disubstituted olefins were excellent substrates for dioxirane-based catalysts. A catalyst was developed based on a chiral ketone that can be synthesized in two steps from D-fructose (see Scheme P-7, compound A). The enantiomeric form can be prepared from L-sorbose in 5 steps. This catalyst, which can be used with oxone or hydrogen peroxide as the oxidant is tolerant of a variety of functional groups. The N-Boc derivative (see Scheme P-7, compound B) exhibits good levels of enantioselectivity with (Z)-disubstituted olefins. Other ketone derivatives do not appear to be as efficient or enantioselective.

Epoxidation of α,β-unsaturated enones and related compounds. The epoxidation of α,β-unsaturated ketones and related carbonyl compounds has been an active area of research in recent years. This epoxidation involves the 1,4-addition of a peroxide to the enone followed by collapse of the intermediate enolate. A variety of catalysts will promote this reaction, including polyleucine catalysts, phase transfer catalysts, lanthanide-BINOL-based catalysts, and main group catalysts. A system involving the stoichiometric epoxidation of enones and nitro alkenes with three equivalents of (R,R)-N-methylpseudoephedrine is noteworthy, because this was the first highly enantioselective epoxidation reactions using diethylzinc and dioxygen to generate the oxidant (see Scheme P-8)

The reaction of diethylzinc with oxygen has had a long and controversial history, and mechanistic work to determine the nature of the oxidation products continues today. The reaction is believed to proceed by insertion of dioxygen into a Zn—C bond to give a zinc peroxy species (see Scheme P-9). In the Enders system, combination of the amino alcohol ligand and diethylzinc in a 1:1 ratio before exposure to dioxygen will not leave any diethylzinc to react with the dioxygen. It was proposed, therefore, that the oxidant in this reaction is zinc bearing the peroxide and the chiral amino alkoxide ligand. This ZnEt2/O2 oxidation reaction was later utilized for the epoxidation of enones a with stoichiometric BINOL polymer. Moderate enantioselectivities and high diastereoselectivities were observed with this system. As shown in Scheme P-9, in cases where there is an excess of dialkylzinc, the oxidant is likely the ethylzinc peroxide, Et-Zn—OOEt. Other mechanistic investigations also support the generation of Et-Zn—OOEt.

Improved methods to synthesize functionalized epoxides are in high demand, because epoxides are among the most valuable and versatile chiral intermediates in organic synthesis. Epoxy alcohols containing three contiguous stereocenters have not been previously prepared directly from achiral starting materials. The inventive subject matter expands the classes of epoxy alcohols that are synthetically accessible.
In our early work on the synthesis of epoxy alcohols with three contiguous stereocenters, we generated allylic alkoxides with substituents on the olefin that led to A1,2 or A1,3 strain in one of the diastereomeric transition states. The allylic zinc alkoxide was formed via enantioselective addition of an alkylzinc reagent to an α,β-unsaturated aldehyde or via an asymmetric vinyl addition with a pre-formed divinylzinc species to a simple aldehyde. Subsequent epoxidation was performed using dioxygen and catalytic Ti(OiPr)4 to provide the desired product with high enantio- and diastereoselectivity. In the absence of either A1,2 or A1,3 strain, moderate diastereoselectivities were obtained.
In our later work, we have expanded the versatility of our one-pot process for the synthesis of epoxy alcohols with three contiguous stereocenters from prochiral starting materials. We now demonstrate that this method is applicable to the synthesis of densely functionalized allylic epoxy alcohols with high enantio-, diastereo-, and chemoselectivity. Additionally, we describe a procedure whereby TBHP can be substituted for dioxygen in the diastereoselective epoxidation step. This new inventive process for tandem addition/diastereoselective epoxidation reactions allows greater control in the oxidation step and is more amenable to scale-up.
Thus, Applicants have developed a highly enantio- and diastereoselective method to synthesize acyclic epoxy alcohols with three contiguous stereocenters in good to excellent yields. The inventive process entails an enantioselective C—C bond-forming reaction to generate allylic alkoxides that are subsequently epoxidized diastereoselectively via a directed epoxidation using standard oxidants. In this process, three new bonds are formed, allowing efficient assembly of complex chiral building blocks. The advantages of these methods are 1) that they circumvent the need to prepare and isolate either racemic or enantioenriched allylic alcohols, 2) the oxidant is generated under the reaction conditions from organozinc reagents and dioxygen, 3) the enantio- and diastereoselectivities are very high for almost all classes of substrates, and 4) the asymmetric C—C bond-forming step can be catalyzed by literally hundreds of catalysts. Like the epoxy alcohols prepared by the Sharpless asymmetric epoxidation, we anticipate that the epoxy alcohols described here will find widespread utility in enantioselective synthesis.